On October 10, 2014, FDA
approved HARVONI a fixed-dose combination tablet of ledipasvir 90
mg, a hepatitis C virus (HCV) NS5A inhibitor, and sofosbuvir 400 mg,
an HCV nucleotide analog NS5B polymerase inhibitor. Harvoni is
indicated for the treatment of chronic hepatitis C (CHC) genotype 1
infection in adults. HARVONI is the first combination pill approved
to treat chronic HCV genotype 1 infection. HARVONI is also the first
approved regimen that does not require administration with
interferon or ribavirin, two FDA-approved drugs also used to treat
HCV infection.

Dosage and Administration:
The recommended dosage of HARVONI is one tablet taken orally once daily with or without food.Recommended Treatment Duration for HARVONIin Patients withCHC Genotype 1

Patient Population

Recommended Treatment Duration

Treatment-naïve with or without cirrhosis

12 weeks*

Treatment-experienced** without cirrhosis

12 weeks

Treatment-experienced** with cirrhosis

24 weeks

* HARVONI for 8 weeks can be
considered in treatment-naïve patients without cirrhosis who have
pre-treatment HCV RNA less than 6 million IU/mL [see Clinical Studies (14)].

No dosage adjustment of HARVONI
is required for patients with mild or moderate renal impairment. No
dose recommendation can be given for patients with severe renal
impairment (estimated Glomerular Filtration Rate [eGFR]
<30 mL/min/1.73m2) or with end stage renal disease (ESRD) due to
higher exposures (up to 20-fold) of the predominant sofosbuvir
metabolite.

No dosage adjustment of HARVONI
is required for patients with mild, moderate, or severe hepatic
impairment (Child-Pugh Class A, B, or C). Safety and efficacy of
HARVONI have not been established in patients with decompensated
cirrhosis.

WARNINGS AND PRECAUTIONS

Risk of Reduced Therapeutic Effect Due to P-gp Inducers
The concomitant use of HARVONI and P-gp inducers
(e.g., rifampin, St. John’s wort) may significantly decrease
ledipasvir and sofosbuvir plasma concentrations and may lead to a
reduced therapeutic effect of HARVONI. Therefore, the use of
HARVONI with P-gp inducers (e.g., rifampin or St. John’s wort) is
not recommended

Related Products Not Recommended
The use of HARVONI with other products containing sofosbuvir (SOVALDI®) is not recommended

Data to Support Approval:
Harvoni’s efficacy was evaluated in three clinical
trials enrolling 1,518 subjects who had not previously received
treatment for their infection (treatment-naive) or had not responded
to previous treatment (treatment-experienced), including subjects
with cirrhosis. Subjects were randomly assigned to receive Harvoni
with or without ribavirin. The trials were designed to measure
whether the hepatitis C virus was no longer detected in the blood at
least 12 weeks after finishing treatment (sustained virologic
response, or SVR), indicating that a subject’s HCV infection has
been cured. See Clinical Studies below for additional details.

ADVERSE REACTIONS
The safety assessment of HARVONI was based on
pooled data from three Phase 3 clinical trials of subjects with
genotype 1 chronic hepatitis C (CHC) with compensated liver disease
(with and without cirrhosis) including 215, 539, and 326 subjects
who received HARVONI for 8, 12 and 24 weeks, respectively.

The most common adverse reactions (≥10%) were fatigue and headache in subjects treated with 8, 12, or 24 weeks of HARVONI.

The Table below lists adverse
reactions (adverse events assessed as causally related by the
investigator, all grades) observed in ≥5% of subjects receiving 8,
12, or 24 weeks treatment with HARVONI in clinical trials.
Themajority of adverse reactions presented in Table 2 occurred at
severity of grade 1. The side-by-side tabulation is to simplify
presentation; direct comparison across trials should not be made due
to differing trial designs.

Bilirubin Elevations: Bilirubin
elevations of greater than 1.5xULN were observed in 3%, <1%, and
2% of subjects treated with HARVONI for 8, 12, and 24 weeks,
respectively.

Lipase Elevations: Transient,
asymptomatic lipase elevations of greater than 3xULN were observed
in <1%, 2%, and 3% of subjects treated with HARVONI for 8, 12,
and 24 weeks, respectively.

Creatine Kinase: Creatine
kinase was not assessed in Phase 3 trials of HARVONI. Isolated,
asymptomatic creatine kinase elevations (Grade 3 or 4) have been
previously reported in subjects treated with sofosbuvir in
combination with ribavirin or peginterferon/ribavirin in other
clinical trials.

DRUG INTERACTIONS
Ledipasvir is an inhibitor of the drug
transporters P-gp and breast cancer resistance protein (BCRP) and may
increase intestinal absorption of coadministered substrates for these
transporters.

Ledipasvir and sofosbuvir are
substrates of drug transporters P-gp and BCRP while GS-331007 is
not. P-gp inducers (e.g., rifampin or St. John’s wort) may decrease
ledipasvir and sofosbuvir plasma concentrations, leading to reduced
therapeutic effect of HARVONI, and the use with P-gp inducers is not
recommended with HARVONI.

The Table below provides a
listing of established or potentially clinically significant drug
interactions. The drug interactions described are based on studies
conducted with either HARVONI, the components of HARVONI (ledipasvir
and sofosbuvir) as individual agents, or are predicted drug
interactions that may occur with HARVONI.

Potentially Significant Drug Interactions:
Alteration in Dose or Regimen May Be Recommended Based on Drug
Interaction Studies or Predicted Interactiona

It is recommended to separate antacid and HARVONI administration by 4 hours.

H2-receptor antagonistsc (e.g., famotidine)

H2-receptor
antagonists may be administered simultaneously with or 12 hours
apart from HARVONI at a dose that does not exceed doses comparable
to famotidine 40 mg twice daily.

Proton-pump inhibitorsc (e.g., omeprazole)

Proton-pump
inhibitor doses comparable to omeprazole 20 mg or lower can be
administered simultaneously with HARVONI under fasted conditions.

Antiarrhythmics:
digoxin

↑ digoxin

Coadministration
of HARVONI with digoxin may increase the concentration of
digoxin. Therapeutic concentration monitoring of digoxin is
recommended when coadministered with HARVONI.

Anticonvulsants:
carbamazepine
phenytoin
phenobarbital oxcarbazepine

↓ ledipasvir
↓ sofosbuvir
↓ GS-331007

Coadministration
of HARVONI with carbamazepine, phenytoin, phenobarbital, or
oxcarbazepine is expected to decrease the concentration of
ledipasvir and sofosbuvir, leading to reduced therapeutic effect
of HARVONI. Coadministration is not recommended.

Antimycobacterials:
rifabutin rifampinc rifapentine

↓ ledipasvir
↓ sofosbuvir
↓ GS-331007

Coadministration
of HARVONI with rifabutin or rifapentine is expected to decrease
the concentration of ledipasvir and sofosbuvir, leading to reduced
therapeutic effect of HARVONI. Coadministration is not
recommended.

Coadministration of HARVONI with rifampin, a P-gp inducer, is not recommended [see Warnings and Precautions (5.1)].

HIV Antiretrovirals:

efavirenz, emtricitabine, tenofovir disoproxil fumarate (DF)

↑ tenofovir

Monitor
for tenofovir-associated adverse reactions in patients receiving
HARVONI concomitantly with the combination of efavirenz,
emtricitabine and tenofovir DF. Refer to VIREAD, TRUVADA, or ATRIPLA
prescribing information for recommendations on renal monitoring.

The
safety of increased tenofovir concentrations in the setting of
HARVONI and a HIV protease inhibitor/ritonavir has not been
established.

Consider alternative HCV or antiretroviral therapy to avoid
increases in tenofovir exposures. If coadministration is
necessary, monitor for tenofovir-associated adverse reactions. Refer
to VIREAD or TRUVADA prescribing information for recommendations
on renal monitoring.

elvitegravir, cobicistat, emtricitabine, tenofovir DF

↑ tenofovir

The
safety of increased tenofovir concentrations in the setting of
HARVONI and the combination of elvitegravir, cobicistat,
emtricitabine and tenofovir DF has not been established.
Coadministration is not recommended.

tipranavir/ritonavir

↓ ledipasvir
↓ sofosbuvir
↓ GS-331007

Coadministration
of HARVONI with tipranavir/ritonavir is expected to decrease the
concentration of ledipasvir and sofosbuvir, leading to reduced
therapeutic effect of HARVONI. Coadministration is not
recommended.

HCV Products:
simeprevirc

↑ ledipasvir
↑ simeprevir

Concentrations
of ledipasvir and simeprevir are increased when simeprevir is
coadministered with ledipasvir. Coadministration of HARVONI
with simeprevir is not recommended.

Herbal Supplements:
St. John’s wort (Hypericum perforatum)

↓ ledipasvir
↓ sofosbuvir
↓ GS-331007

Coadministration of HARVONI with St. John’s wort, a P-gp inducer is not recommended [see Warnings and Precautions (5.1)].

HMG-CoA Reductase Inhibitors:
rosuvastatin

↑ rosuvastatin

Coadministration
of HARVONI with rosuvastatin may significantly increase the
concentration of rosuvastatin which is associated with increased
risk of myopathy, including rhabdomyolysis. Coadministration of
HARVONI with rosuvastatin is not recommended.

a. This table is not all inclusive.
b. ↓ = decrease, ↑ = increase

c. These interactions have been studied in healthy adults

Drugs without Clinically Significant Interactions with HARVONI
Based on drug interaction studies conducted with the
components of HARVONI (ledipasvir or sofosbuvir) or HARVONI, no
clinically significant drug interactions have been either observed
or are expected when HARVONI is used with the following drugs
individually: abacavir, atazanavir/ritonavir, cyclosporine,
darunavir/ritonavir, efavirenz, emtricitabine, lamivudine, methadone,
oral contraceptives, pravastatin, raltegravir, rilpivirine,
tacrolimus, tenofovir disoproxil fumarate, or verapamil. See Table
above for use of HARVONI with certain HIV antiretroviral regimens.

Clinical StudiesTreatment-Naïve Adults without Cirrhosis - ION-3 (Study 0108)
ION-3 was a randomized, open-label trial in
treatment-naïve non-cirrhotic subjects with genotype 1 CHC. Subjects
were randomized in a 1:1:1 ratio to one of the following three
treatment groups and stratified by HCV genotype (1a vs 1b): HARVONI
for 8 weeks, HARVONI for 12 weeks, or HARVONI + ribavirin for 8
weeks.

Demographics and baseline
characteristics were balanced across the treatment groups. Of the 647
treated subjects, the median age was 55 years (range: 20 to 75);
58% of the subjects were male; 78% were White; 19% were Black; 6%
were Hispanic or Latino; mean body mass index was 28 kg/m2 (range:
18 to 56 kg/m2); 81% had baseline HCV RNA levels greater than or
equal to 800,000 IU/mL; 80% had genotype 1a HCV infection; 73% had
non-C/C IL28B alleles (CT or TT).

Table 6 presents the response
rates for the HARVONI treatment groups in the ION-3 trial after 8
and 12 weeks of HARVONI treatment. Ribavirin was not shown to
increase the response rates observed with HARVONI. Therefore, the
HARVONI + ribavirin arm is not presented in Table 6.

a. The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment assessment.

b. Other includes subjects who did not achieve SVR and did not meet virologic failure criteria (e.g., lost to follow-up).

c. One subject without a confirmed subtype for genotype 1 infection was excluded from this subgroup analysis.

The treatment difference between
the 8-week treatment of HARVONI and 12-week treatment of HARVONI was
–2.3% (97.5% confidence interval –7.2% to 2.5%). Among subjects
with a baseline HCV RNA <6 million IU/mL, the SVR was 97%
(119/123) with 8-week treatment of HARVONI and 96% (126/131) with
12-week treatment of HARVONI.

a. HCV RNA values were determined using the Roche TaqMan Assay; a subject's HCV RNA may vary from visit to visit.

Treatment-Naïve Adults with or without Cirrhosis - ION-1 (Study 0102)
ION-1 was a randomized, open-label trial that
evaluated 12 and 24 weeks of treatment with HARVONI with or without
ribavirin in 865 treatment-naïve subjects with genotype 1 CHC
including those with cirrhosis. Subjects were randomized in a
1:1:1:1 ratio to receive HARVONI for 12 weeks, HARVONI + ribavirin
for 12 weeks, HARVONI for 24 weeks, or HARVONI + ribavirin for 24
weeks. Randomization was stratified by the presence or absence of
cirrhosis and HCV genotype (1a vs 1b). The interim primary endpoint
analysis for SVR included all subjects enrolled in the 12-week
treatment groups (N=431). SVR rates for all subjects enrolled in the
24-week treatment groups (N=434) were not available at the time of
interim analysis.

Demographics and baseline
characteristics were balanced across the treatment groups. Of the 865
treated subjects, the median age was 54 years (range: 18 to 80);
59% of the subjects were male; 85% were White; 12% were Black; 12%
were Hispanic or Latino; mean body mass index was 27 kg/m2 (range:
18 to 48 kg/m2); 79% had baseline HCV RNA levels greater than or
equal to 800,000 IU/mL; 67% had genotype 1a HCV infection; 70% had
non-C/C IL28B alleles (CT or TT); and 16% had cirrhosis.

Table 8 presents the response
rates for the treatment group of HARVONI for 12 weeks in the ION-1
trial. Ribavirin was not shown to increase response rates observed
with HARVONI. Therefore, the HARVONI + ribavirin arm is not
presented in Table 8.

Table 8 Study ION-1:
Response Rates after 12 Weeks of Treatment in Treatment-Naïve
Subjects with Genotype 1 CHC with and without Cirrhosis

HARVONI 12 Weeks (N=214)

SVRa

99% (210/213)

Outcome for Subjects without SVR

On-Treatment Virologic Failurea

0/213

Relapsea,b

<1% (1/212)

Othera,c

1% (2/213)

a. Excluding one subject with genotype 4 infection.

b. The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment assessment.

c. Other includes subjects who did not achieve SVR and did not meet virologic failure criteria (e.g., lost to follow-up).

Response rates for selected subgroups are presented in Table 9.

Table 9 Study ION-1:
SVR Rates for Selected Subgroups after 12 Weeks of Treatment in
Treatment-Naïve Subjects with Genotype 1 CHC with and without
Cirrhosis

HARVONI 12 Weeks (N=214)

Genotypea

Genotype 1a

98% (142/145)

Genotype 1b

100% (67/67)

Cirrhosisb

No

99% (176/177)

Yes

94% (32/34)

a. One subject without a
confirmed subtype for genotype 1 infection and one subject with
genotype 4 infection were excluded from this subgroup analysis.

b. Subjects with missing cirrhosis status were excluded from this subgroup analysis.

14.3 Clinical Trials in Subjects Who Failed Prior Therapy

Previously-Treated Adults with or without Cirrhosis - ION-2 (Study 0109)

ION-2 was a randomized, open-label trial that
evaluated 12 and 24 weeks of treatment with HARVONI with or without
ribavirin in genotype 1 HCV-infected subjects with or without
cirrhosis who failed prior therapy with an interferon-based regimen,
including regimens containing an HCV protease inhibitor. Subjects
were randomized in a 1:1:1:1 ratio to receive HARVONI for 12 weeks,
HARVONI + ribavirin for 12 weeks, HARVONI for 24 weeks, or HARVONI +
ribavirin for 24 weeks. Randomization was stratified by the presence
or absence of cirrhosis, HCV genotype (1a vs 1b) and response to
prior HCV therapy (relapse/breakthrough vs nonresponse).

Demographics and baseline
characteristics were balanced across the treatment groups. Of the
440 treated subjects, the median age was 57 years (range: 24 to 75);
65% of the subjects were male; 81% were White; 18% were Black; 9%
were Hispanic or Latino; mean body mass index was 28 kg/m2 (range:
19 to 50 kg/m2); 89% had baseline HCV RNA levels greater than or
equal to 800,000 IU/mL; 79% had genotype 1a HCV infection; 88% had
non-C/C IL28B alleles (CT or TT); and 20% had cirrhosis. Forty‑seven
percent (47%) of the subjects failed a prior therapy of pegylated
interferon and ribavirin. Among these subjects, 49% were
relapse/breakthrough and 51% were non-responder. Fifty-three percent
(53%) of the subjects failed a prior therapy of pegylated interferon
and ribavirin with an HCV protease inhibitor. Among these
subjects, 62% were relapse/breakthrough and 38% were non-responder.

Table 10 presents the response
rates for the HARVONI treatment groups in the ION-2 trial. Ribavirin
was not shown to increase response rates observed with HARVONI.
Therefore, the HARVONI + ribavirin arms are not presented in Table
10.

Table 10 Study ION-2: Response Rates after 12 and 24 Weeks of Treatmentin Subjects with Genotype 1 CHC with or without Cirrhosis who Failed Prior Therapy

HARVONI
12 Weeks
(N=109)

HARVONI
24 Weeks
(N=109)

SVR

94% (102/109)

99% (108/109)

Outcome for Subjects without SVR

On-Treatment Virologic Failure

0/109

0/109

Relapsea

6% (7/108)

0/109

Otherb

0/109

1% (1/109)

a. The denominator for relapse is the number of subjects with HCV RNA <LLOQ at their last on-treatment assessment.

b. Other includes subjects who did not achieve SVR and did not meet virologic failure criteria (e.g., lost to follow-up).

Among the subjects with available
SVR12 and SVR24 data (206/218), all subjects who achieved SVR12 in
the ION-2 study also achieved SVR24.

Response rates and relapse rates for selected subgroups are presented in Tables 11 and 12.